Endovascular graft coatings

ABSTRACT

An endovascular graft, e.g., having both an expandable stent portion and a stent cover portion positioned within and/or surrounding the expandable portion, the graft itself and/or a stent cover portion being coated with a bioactive agent adapted to promote initial thrombus formation, preferably followed by long term fibrous tissue ingrowth. The endovascular graft addresses concerns regarding endoleaking by permitting the graft to be deployed and used in a manner that promotes a short term hemostatic effect in the perigraft region. This short term effect can, in turn, be used to promote or permit long term fibrous tissue ingrowth. Particularly where the stent cover portion is prepared from a porous material selected from PET and ePTFE, the bioactive agent can include a thrombogenic agent such as collagen covalently attached in the form of a thin, conformal coating on at least the outer surface of the stent cover. An optimal coating of this type is formed by the activation of photoreactive groups provided by either the cover material itself, by the bioactive agent itself, and/or by a linking agent.

TECHNICAL FIELD

The present invention relates to endovascular grafts, particularlyincluding endovascular grafts that include both a rigid and expandablestent portion and a stent cover portion. In another aspect, theinvention relates to the manufacture and use of such devices.

BACKGROUND OF THE INVENTION

Endovascular grafts (also known by such terms as endoluminal grafts,endografts, endovascular stent grafts, expandable transluminal grafts,vascular endoprostheses, and intravascular stent grafts) can be broadlydefined as vascular grafts that are positioned within existing veins andarteries. As such, they can be contrasted with non-endovascular grafts,more commonly known as vascular grafts, which can be provided in theform of either bypass grafts or interpositional grafts. As compared toendovascular grafts, vascular grafts are instead positioned in a mannerthat replaces a portion (interpositional), or provides a shunt (bypass)between one or more portions, of veins or arteries, or between an arteryand a vein. Endovascular grafts have been gaining increased attention inrecent years, particularly for use in treating aneurysms such as aorticaneurysms. An aneurysm is generally defined as a sac formed by thepathologic dilation of an artery or vein beyond its normal physiologicaldiameter.

Abdominal aortic aneurysms (AAA), which are aneurysms of the aorta inthe abdominal cavity, are of particular interest, as are thoracicaneurysms. See, for example, “Endovascular Graft Treatment of AorticAneurysms: Future Perspectives”, Kondo, et al., Nippon Geka GakkaiZasshi 100(8):506-12, (1999) (abstract), which describes the manner inwhich the use of endovascular grafts to treat aortic aneurysms, firstclinically applied by Parodi et al., has gained popularity. Although theuse of endovascular grafts were initially limited to high-risk patients,their indications have been gradually expanded.

A typical approach involves the initial placement of an endovasculargraft in the aneurysm, in order to exclude the aneurysmal sac whilemaintaining the arterial blood flow, thus preventing further dilatationand possible rupture of the vessel. Over recent years, however, Kondo etal. and others have described various instances in which aneurysms,excluded completely during surgery, can became patent due to“endoleaking”, a phenomenon that can occur immediately or even yearsafter the procedure. Considering these and other features, somepractitioners hold that endovascular grafting should continue to belimited to high-risk patients. In most cases, however, and particularlywith thoracic aortic aneurysms, endovascular treatment is considered auseful alternative for those with localized aneurysms because of thehigh perioperative morbidity accompanying conventional open repair.

With regard to the continuing concern about endoleaking, however, seealso Wain, et al., “Endoleaks after Endovascular Graft Treatment ofAortic Aneurysms: Classification, Risk Factors, and Outcome”, J Vasc.Surg. 27(l):69-78 (1998) (abstract), which also describes the manner inwhich incomplete endovascular graft exclusion of an abdominal aorticaneurysm can result in endoleaking.

Finally, see Jacobowitz et al., “The Significance and Management of theLeaking Endograft”, Semin. Vasc. Surg. 12(3):199-206 (1999) (abstract),which defines endoleaking as the persistence of blood flow outside thelumen of an endograft, but within an aneurysm sac or adjacent vesselbeing treated by the graft. Diagnosis may be difficult, and treatmentremains somewhat controversial. The article discusses the clinicalsignificance and appropriate management of endoleaks within the contextof current understanding of this phenomenon.

On another subject, the literature provides several examples of the useof hemostatic agents in the course of surgery. Generally, “hemostasis”can be defined as the interruption of blood flow to any anatomical area.Hemostasis is typically caused by biological processes (such as clotformation) or surgical procedures (including manual compression). Theword “thrombosis”, in turn, is generally used to refer to hemostasisproduced by clot formation. A variety of commercial hemostatic productsexist that promote localized clot formation, and which generallyincorporate one or more thrombogenic proteins. Such proteins includethrombin and certain collagens, which are known to activate plateletsand/or fibrin formation (Colman, R. W., “Mechanisms of ThrombusFormation and Dissolution”, Cardiovascular Pathol. 2:23S-31S (1993). Theprimary use, currently, for such hemostatic products is to halt diffusebleeding from wound sites, vascular punctures, or other surgicalprocedures. Examples of such products include FluoSeal Matrix® (FusionMedical Technologies, Mountain View, Calif.) and CoStasis® (CohesionCorporation, Palo Alto, Calif.), each of which is composed of thrombinmixed with bovine collagen. Angio-Seal® (Kensey Nash Corporation, Exton,Pa.) is a three-component preparation, one of which is bovine skincollagen. Each of the above hemostatic products consists of two or morecomponents, which are mixed immediately before use.

There is a dichotomy in the medical device industry with regard to theuse of thrombogenic coatings on grafts, depending in large part on thediameter of the graft involved. Small diameter grafts (e.g., less thanabout 6 mm in diameter) are typically not provided with thrombogeniclumenal surfaces, since to do so would tend to promote the rapidaccumulation of thrombi on the surface, and/or to speed the invasion andproliferation of myofibroblasts (leading to intimal hyperplasia), eitheror both of which processes can tend to occlude the graft itself.Typically, therefore, nonthromogenic coatings and materials are commonlypreferred for usein preparing small diameter bypass grafts (e.g.,peripheral and coronary artery grafts). See, for instance, Ozaki, etal., “New Stent Technologies”, Prog. Cardiovasc. Dis., 39(2):129-40(September-October 1996) (abstract).

Large diameter vascular grafts, and particularly those intended for useas aortic vascular grafts, are typically not prone to being occluded ina similar fashion. To the contrary, these grafts have a differentinherent problem, namely, the tendency of blood to seep through what aretypically porous materials used to form the graft itself. Hence thesegrafts can be, and often are, coated with a hemostatic agent that actsas a barrier to blood flow by physically occluding the pores. The poresof materials such as polyethylene terephthalate (PET), for instance, canbe plugged by a variety of methods, including, 1) by preclotting thegraft (e.g., dipping the grafts in the patients own blood, to permitclots to form in the pores), or 2) by filling the pores with materialssuch as crosslinked gelatins.

Hemostatic barrier agents are therefore occasionally used in connectionwith conventional large diameter vascular (though non-endovascular)grafts. Guidoin, et al., for instance, evaluated three clinically-usedPET grafts (available under the tradenames Gelseal™, Hemashield™, andTascon™) whose pores were filled with gelatin or collagen (“CollagenCoated Polyester Arterial Prostheses: An Evaluation”,Transplantation/Implantation Today, pp. 21-25, February 1988). Withthese grafts, the applied gelatin or collagen was crosslinked witheither formaldehyde or glutaraldehyde. When evaluated in vitro, thecollagen or gelatin “coatings” decreased water flow through the graftwalls by more than 99%, therefore confirming that each provided animmediate physical barrier to blood flow. Additional barrier coatingsthat are reported to block blood flow through the walls of polyestergrafts include albumin and alginate.

Simlarly, a variety of other coatings have been described for use onlarge diameter arterial (though again, typically non-endovascular)grafts. See for instance, Marios, et al. “In Vivo Biocompatibility andDegradation Studies of Polyhydroxyoctanoate in the Rat: A New Sealantfor the Polyester Arterial Prosthesis”, Tissue Eng., 5(4):369-386 (1999)(abstract); Ben Slimane, et al., “Albumin-coated Polyester ArterialProstheses: Is Xenogenic Albumin Safe?”, Biomater. Artif. Cells Artif.Organs. 15(2):453-81 (1987) (abstract): Lee, et al., “Development andCharacterization of an Alginate-impregnated Polyester Vascular Graft.”,J. Biomed. Mater. Res., 36(2):200-8 (August 1997) (abstract); Chafke, etal., “Albumin as a Sealant for a Polyester Vascular Prosthesis: ItsImpact on the Healing Sequence in Humans.”, J. Cardiovasc. Surg.,(Torino) October;37(5):431-40 (1996)(abstract); and Ukpabi, et al.(abstract). “The Gelweave Polyester Arterial Prosthesis”, Can. J. Surg.,38(4):322-3 (August 1995) (abstract).

For reasons that include those above, therefore, it appears thatthrombogenic agents have rarely, if ever, been used in any connectionwith endovascular grafts, and then typically for reasons quite unrelatedto either coating the article itself, or in turn, for preventingendoleaking. See, for instance, Henry, et al., “A New Access SiteManagement Tool: the Angio-Seal Hemostatic Puncture Closure Device.”, J.Endovasc. Surg., 2(3):289-96 (August 1995) (abstract) suggests that withthe increasing number of percutaneously applied endovascular therapies,the incidence of access-related vascular complications can be expectedto rise, particularly in association with those techniques requiringlarge sheaths or anticoagulation. Recognizing the need for a safe, easyto use, and effective hemostatic technique to replace thelabor-intensive method of manual compression, the authors describe abioabsorbable, sheath-delivered vascular device (Angio-Seal) thatdeposits a small collagen plug within the arterial wall to mechanicallyseal the puncture defect.

On a separate subject, long-term responses of the body to variousmaterials, including those used to fabricate endovascular grafts, havebeen studied as well. See, for instance Shin, et al., “Histology andElectron Microscopy of Explanted Bifurcated Endovascular Aortic Grafts:Evidence of Early Incorporation and Healing.”, J. Endovasc. Surg.,6(3):246-50 (August 1999)(abstract), which reports an examination ofexplanted bifurcated endovascular aortic grafts for histologic evidenceof early healing and incorporation.

However, there are many references in the art that describe theundesirable role of “intimal hyperplasia” in promoting occlusions. See,for instance, Gates and Kent, 1994 in “Alternative Bypass Conduits andMethods for Surgical Coronary Revascularization”. Few references, ifany, however, describe this or any other process of long term fibroustissue ingrowth as being a positive event to be encouraged with a bypassgraft, let alone with an endovascular graft.

Finally, and on yet another subject, the assignee of the presentinvention has previously described a variety of applications for the useof photochemistry, and in particular, photoreactive groups, e.g., forattaching polymers and other molecules to support surfaces. See, forinstance, U.S. Pat. Nos. 4,722,906, 4,979,959, 5,217,492, 5,512,329,5,563,056, 5,637,460, 5,714,360, and 5,744,515.

In spite of these various advances, however, to date there appears tohave been little if any progress made with respect to the solving theproblem of endoleaking, per se. This in spite of the fact that thewidespread acceptance and true value of endovascular grafts are likelyto remain hampered until this problem is resolved.

SUMMARY OF THE INVENTION

The present invention comprises an endovascular graft, e.g., in the formof an expandable stent portion and a stent cover portion positionedeither within and/or surrounding the expandable portion, the graft(e.g., stent cover portion) being coated with a bioactive agent adaptedto promote initial thrombus formation when the graft is positionedwithin a blood vessel. Optionally, and preferably, the coated stentand/or cover of the present invention also provides improved fibroustissue ingrowth over time. The term “fibrous tissue ingrowth”, as usedherein, refers to the repair process that occurs as a response to injury(in this case, the placement of an endovascular graft), by which thebody provides new tissue containing a high density of collagen fibers.

In a preferred embodiment, the stent cover portion is prepared from aporous material selected from PET or expanded polytetrafluoroethylene(ePTFE), and the bioactive agent comprises a thrombogenic agent such ascollagen. In one preferred embodiment, for instance, the bioactive agentis covalently attached in the form of a thin (e.g., one to threemonolayers), and conformal coating on at least the outer surface of astent cover, most preferably by the activation of photoreactive groupsprovided by either the cover material itself, by the bioactive agentitself, and/or by a linking agent. In another aspect, the inventionrelates to a method of preparing an endovascular graft that includescoating the graft with a bioactive agent in the manner described herein,as well as a method of using such an endovascular graft to avoidendoleaking upon placement of the graft in vivo. With the endovasculargraft in place, and continuity of the vascular lumen reestablished, thecoating is preferably adapted to then permit, if not encourage, longterm fibrous ingrowth to occur into the stent and/or stent cover. Hencethe invention further provides a graft as described herein, positionedwithin a vein or artery, and preferably, including new fibrous tissuegrown into the pores of the graft.

A “conformal” coating, as used herein, refers to one in which thebioactive agent has been carefully attached (e.g., to the individualfibers making up the material, without plugging the pores therein) in amanner that provides an optimal combination of low bulk and effectivethrombogenic effect in vivo. By contrast, non-conformal coatings ofbioactive agents on a material may provide a thrombogenic effect, buttend to be too bulky to deliver in the manner required. In turn, aconformal coating that provides an inadequate amount of agent, or thatprovides the agent in a form not suitably tenacious for its intendeduse, may permit the graft to be delivered in a minimally invasivefashion, but will not tend to provide bioactivity in the desired region,or in an effective amount and duration. Hence the present inventionprovides an optimal balance between such parameters as bulk, coatingdensity and tenacity, and ultimately, bioactivity in vivo.

DETAILED DESCRIPTION

The method of the present invention can be used in connection with anysuitable endovascular graft. Such grafts are typically inserted into thelumen of a blood vessel to form a barrier between the aneurysm andcirculating blood, for instance, to treat abdominal aortic aneurysms.The word “perigraft”, as used in this context, will refer to theposition situated or occurring around an endovascular graft, such that“endoleaking” (also known as perigraft leaking), can be defined as bloodflowing around the endovascular graft and into the aneurysm itself. Suchblood flow, therefore, is generally within the perigraft space betweenthe ablumenal surface of the endovascular graft and the surroundingblood vessel. The method and apparatus of this invention can be used toprovide acute perigraft hemostasis, that is, hemostasis in the perigraftspace, within on the order of an hour or less, and more preferablywithin several minutes or less, of endovascular graft placement.

Given the present description, those skilled in the art will be able toidentify and incorporate a variety of bioactive agents for use ascoatings of the present invention. Preferred bioactive agents, forinstance, can be selected from those materials presently used assealants or hemostatic agents in the course of surgery, and preferablythose having thrombogenic qualities. The word “thrombosis”, andinflections thereof, will be used herein to refer to hemostasis producedby clot formation, and “thrombogenic agents”, for instance, to proteinsand other agents (e.g., positively charged agents such as chitosan) thatactively promote clot formation.

In a preferred embodiment a “bioactive agent” of the present inventionwill be thrombogenic under the conditions of use. Those skilled in theart will appreciate the manner in which such agents can be identified,coated and used. Preferably, for instance, both the selection of anappropriate bioactive agent and the effectiveness of a coating of theagent upon a stent cover can be evaluated using a “Test Assay” asdescribed herein.

Bioactive agents suitable for use in the present invention include thosehaving a specific action within the body, as well as those havingnonspecific actions. Specific action agents are typically proteinaceous,e.g., including thrombogenic types and/or forms of collagen, thrombinand fibrinogen (each of which tend to provide an optimal combination ofactivity and cost), as well as elastin and von Willebrand factor (whichtend to be less active and/or more expensive agents), and activeportions and domains of each of these agents. Thrombogenic proteinstypically act by means of a specific interaction with either plateletsor enzymes that participate in a cascade of events leading eventually toclot formation.

Agents having a nonspecific thrombogenic action are generally positivelycharged molecules, e.g., polymeric molecules such as chitosan,polylysine, poly(ethylenimine) or acrylics polymerized from acrylamideor methacrylamide which incorporate positively-charged groups in theform of primary, secondary, or tertiary amines or quaternary salts, ornon-polymeric agents such as benzalkonium chloride(alkyldimethylbenzylammonium chloride) and TDMAC(tridodecylmethylammonium chloride). Positively charged hemostaticagents promote clot formation by a non-specific mechanism, whichincludes the physical adsorption of platelets via ionic interactionsbetween the negative charges on the surfaces of the platelets and thepositive charges of the agents themselves.

The word “collagen”, as used herein, will refer both to native collagen,in which the molecules substantially retain their native triple helixstructure, as well as “gelatin”, in which the structure has beendenatured, resulting in the partial or complete dissociation of thetriple helix strands. Native collagens include one or more members of aclass of at least 14 proteins, each of which includes a distinctivetriple helix as a part of its structure. Type I collagen is the mostabundant animal protein, is readily isolated, and has useful physicaland biological properties. Bovine tendon and skin are two common sourcesof this collagen, with nearly pure type I collagen being obtained fromtendons and skin yielding a mixture of 5% type III and 95% type Icollagen. For the above reasons, type I (±5% type III) is the collagenmost commonly used to formulate medical materials (Pachence, J. M.,“Collagen-Based Devices for Soft Tissue Repair”, J. Biomed. Mater. Res.33:35-40, 1996). Type I (native) collagen promotes soft tissue repairwhen incorporated into several types of wound dressings. Collagen type Iis also capable of promoting the attachment of fibroblasts and theproduction of new collagen by such attached fibroblasts.

Another commonly available hemostatic protein is von Willebrand factor,which is reported to mediate the adhesion of platelets to collagen typesI, III and VI (Cruz et al., “Interaction of the von Willebrand Factor(vWF) with Collagen. Localization of the Primary Collagen-Binding Siteby Analysis of Recombinant vWF A Domain Polypeptides”, J. Biol. Chem.,270:10822-10827, 1995).

Elastin and fibrinogen are two additional proteins that are abundant inthe body, hemostatic, and able to mediate wound healing. Fibrinogendirectly promotes platelet aggregation and its product (fibrin) servesas a scaffold for wound healing (Colman, above). The activities ofelastin are indirect and are due to its ability to bind types I and IIIcollagens (Dutoya et al., “Unexpected Original Property of ElastinDerived Proteins: Spontaneous Tight Coupling with Natural and SyntheticPolymers” Biomaterials 19,147-155 (1998), which in turn are hemostaticand mediate wound healing.

A hemostatic agent will typically be immobilized in an amount betweenabout 0.01 μg/cm² to about 50 μg/cm² of graft cover material, preferablybetween about 0.05 μg/cm ² to about 10 μg/cm², and most preferablybetween about 0.1 μg/cm² to about 5 μg/cm². Native thrombogenic proteinswill typically be active at about the middle of the preferred range(e.g., between about 1 μg/cm² and about 10 μg/cm²), while active peptidesegments are likely to be active at about 10-fold lower concentration.Positively charged reagents may require levels toward the upper ends ofthese concentration ranges, since they tend to act in a non-specificmanner.

The endovascular grafts addressed by the application of this inventionwill typically include both a stent portion adapted to be delivered in acondensed form, and expanded in situ, as well as a cover portion adaptedto substantially prevent the flow of blood from the lumen of the vesselitself through the walls and toward the ablumenal surface of theendovascular graft. The cover, in turn, can be of any suitable style ordimensions, e.g., it can cover the internal and/or external portions orsurfaces, of some or substantially the entire length, of the expandablestent portion. Optionally, a reagent of this invention can also be usedto coat an expandable metallic or polymeric stent with a thrombogeniclayer, i.e., without employing or coating a stent cover. Several suchstents can be deployed, for instance, in an overlapping or superimposedmanner, such that they effectively provide a substantially impermeablebarrier to the flow of blood components. In such an embodiment, one orall of the overlapping stents can be provided with a thrombogenicsurface in the manner described herein.

Endovascular grafts in conventional use today typically include anexpandable mesh tube covered with a fabric-like cover. The expandableportions are generally formed of a “shape memory” alloy such as nickeltitanium alloys (referred to commonly as “nitinol”). Endovascular graftsformed of such materials (including both the stent and cover portions)can be collapsed to form a small diameter tube (e.g., on the order oftwo mm or less overall diameter), which can be expanded using forceand/or by self-expansion, to form a larger diameter tube in situ (e.g.,between about six mm and about thirty mm).

The method of the present invention can be adapted for use with avariety of available endovascular grafts and endovascular graft designs,and in particular with “endovascular grafts” that include an expandable(e.g., self-expanding or pressure-expandable) stent portion which isaffixed to or formed within a pliable tubular graft. Because of theirradial compressibility/expandability, these grafts are particularlyuseful in applications wherein it is desired to insert the graft into ananatomical passageway (e.g., blood vessel) while the graft is in aradially compact state, and to subsequently expand and anchor the graftto the surrounding wall of the anatomical passageway.

Typically, the stent portions of such endovascular grafts are providedin the form of metallic mesh tubes, e.g., formed in various styles andpatterns of intersecting metallic wires, strands or bars, into astructure that permits the endovascular graft to be collapsed orcondensed for purposes of its delivery, and once in place, expandedtowards its fullest desired diameter (e.g., using a balloon positionedwithin the device). Once expanded, the resultant endovascular graftsprovide a lumen sufficient to restore function to the vessel, andprovide an external (ablumenal) surface that abuts the internal surfaceof the original vessel itself. Materials commonly used or suggested foruse as endovascular graft covers include polytetrafluroethylene,expanded polytetrafluroethylene, polyethylene terephthalate,polycarbonate, polyethyelene, polyurethane, as well as biodegradablematerials such as elastin, polyglycolic acid, and polylactic acid.

Recent methods have been developed for introducing and implantingtubular prosthetic vascular grafts within the lumen of a blood vessel,by percutaneous or minimal incision means. Such endovascularimplantation initially involves translumenal delivery of the graft, in acompacted state, by way of a catheter or other transluminally advancabledelivery apparatus. Thereafter, the graft is radially expanded andanchored to the surrounding blood vessel wall, thereby holding the graftat its intended site of implantation within the host blood vessel. Anaffixation method, such as proximal and distal uncovered stent portionssized to over-expand and push into the native vessel wall, can be usedto anchor at least the opposite ends of the generally tubular graft tothe surrounding blood vessel wall.

One particular application for endovascular grafts of this type is inthe treatment of vascular aneurysms, without the need for open surgicalaccess and resection of the aneurysmic blood vessel. Also, suchendovascular grafts can also be used to treat occlusive vasculardisease-especially, in cases where the graft is constructed in such amanner that the tubular graft material forms a complete barrier betweenthe endovascular graft and the blood flowing through the blood vessel.In this manner the tubular graft material can serve as a smooth,biologically compatible, inner “covering” for the endovascular graft,thereby serving to: a) prevent turbulent blood-flow as the blood flowsover the wire members or other structural material of which theendovascular graft is formed; b) prevent immunologic reaction to themetal or other material of which the endovascular graft is formed; andc) provide a barrier to separate a diseased or damaged segment of bloodvessel from the blood-flow passing therethrough. The prevention ofturbulent blood-flow and/or immunologic reaction to the endovasculargraft material are particularly desirable since both phenomena arethought to be associated with thrombus formation and/or restenosis ofthe blood vessel.

Coated endovascular grafts of the present invention are particularlyuseful, for instance, in repair of the aorta, vena cava, femoral arteryand vein, iliac artery and vein, subclavian artery and vein, tibialartery, peroneal artery, saphenous vein, pulmonary artery and vein,coronary arteries, carotid artery, jugular vein, radial artery,subclavian artery.

In the method of this invention, a bioactive agent is coated on anendovascular graft cover in order to provide the desired level ofthrombogenicity (acute hemostasis) under the conditions of deploymentand use in vivo. In a preferred embodiment, the coating provides anoptimal combination of such properties as low bulk, coating density,coating tenacity, and bioactivity in vivo. Given these functionalrequirements, and depending on such variables as the type ofendovascular graft cover, the method of endovascular graft deployment,and the bioactivity of the agent itself, those skilled in the art willbe able to determine an optimal manner of coating a endovascular graftcover for any particular combination of bioactive agent, endovasculargraft cover material, and endovascular graft design.

The coating agent of this invention can be coated on the endovasculargraft cover in any suitable manner (e.g., by dipping, spraying orbrushing) within the skill of those in the relevant art. In a preferredembodiment, a bioactive agent is first derivatized with photogroups, andthen brought into contact (i.e., sufficient proximity to permit binding)with a previously formed graft cover. The photoreactive groups are thenenergized via an external stimulation (e.g., exposure to a suitablelight source) to form via free active specie generation, a covalent bondbetween the agent and either another reagent molecule, the coversurface, or chemical moieties present in the coating solution itselfand/or upon the surface. This coating method can be referred to as a“one step” method, since photoreactive coupling chemistry attaches thebioactive agent to the cover surface, and no subsequent steps (otherthan perhaps washing steps) are required. The external stimulation thatis used is preferably in the form of electromagnetic radiation, andpreferably is radiation in the ultraviolet, visible or infrared regionsof the electromagnetic spectrum.

The coating can be applied at the time of manufacture of the materialitself, in the course of its fabrication into a endovascular graftcover, and/or at the time of use. Suitable non-photoreactive methods forcoating such materials (in either a covalent or noncovalent fashion) aredescribed in Hoffman, A. S., “Immobilization of Biomolecules and Cellson and within Polymeric Biomaterials”, Clin. Mat. 11:61-66 (1992), thedisclosure of which is incorporated herein by reference.

One suitable method for covalent coupling to the surface involves aninitial step of adding a reactive group to the surface (e.g., amine,carboxyl, etc.), for instance, by the application of ionizing radiation,plasma gas discharge, chemical derivatization, etc. This can be followedby the use of thermochemical crosslinking reagents to couple thehemostatic agent to the surface bound reactive group. Yet other methodscan be used to form films around fibers, for instance, usingthermochemical crosslinking reagents to crosslink thin films of thehemostatic agent around individual fibers. Other methods, thoughgenerally less preferred, can be used to enhance the adsorption ofcoating agent to the material, e.g., denucleation in ethanol followed byadsorption from phosphate buffered saline (PBS) (see, e.g., Poole-Warrenet. al., J. Biomed. Mater. Res., 30:221-229 (1996) used this method toadsorb fibronectin onto ePTFE). In yet another approach, hydrophobic“anchor” groups are added to the hemostatic agent to increase adsorptionto implant device polymers. Haverstick, et .al., Trans. Soc. Biomat.,22:287 (1999) have used this method to immobilize ECM peptides ontohydrophobic substrates.

In one preferred embodiment, for instance, a thin, conformal coating ofthis invention is provided on the perigraft surface (i.e., the external,vessel-contacting surface of the graft itself) and optionally within thepores of the material itself. The coating agent is preferably not coatedon the interior (luminal) surface of the graft, since its presence thereis likely to be inconsequential at best, and detrimental at worst. Thecoating agent can be coated, for instance, as a thin conforming layer onand/or around individual fibers of the graft.

A coating of the present invention will typically not add significantlyto the bulk of the graft, or interfere with its delivery via a catheter.Nor, in turn, will it interfere with (and preferably will enhance) longterm ingrowth by fibrous tissue. Surprisingly, it has been found thatbioactive agents can be coated in a manner that provides suitablephysical qualities (e.g., bulk, tenacity), chemical qualities (e.g.,biocompatibility), and biological qualitites (e.g., hemostatic activity)sufficient to lessen or avoid endoleaking yet permit the graft to bedelivered and positioned in a minimally invasive fashion (typically,through a catheter). In a preferred embodiment, an effective coating ofthis invention adds about 25%, or less, preferably about 10%, or less,and most preferably about 5%, or less, to the original thickness of thematerial used as the stent cover portion. In this manner the resultantendovascular graft can be packaged and delivered in substantially themanner originally intended by the manufacturer.

Typically, it is not desirable to have the coating fill the pores withinthe graft. The coating agent can be attached to the surface in anysuitable manner, e.g., it can be passively adsorbed, entrapped, orcovalently bound to the surface itself, or to a coating that is itselfpositioned within or upon the surface, so long as the coating issufficiently tenacious and effective for its intended use (e.g., is notremoved by flowing blood or by the abrasion associated with delivery viacatheter). As such, the coating can be in any suitable form, e.g.,impregnated within the pores of the cover itself, as a discrete layerthereon, or as a coating (e.g., film) around the individual fibers of afabric.

Preferably, the coating agent is covalently atached by photochemicalmeans, e.g., in the manner described in the approaches described in U.S.Pat. Nos. 4,722,906, 4,979,959, 5,217,492, 5,512,329, 5,563,056,5,637,460, 5,714,360, and 5,744,515. In aparticularly preferredembodiment, for instance, various types of collagen can bephotoderivatized (e.g., with BBA-EAC-NOS) and radiolabeled usingprotocols for derivatizing proteins as described in U.S. Pat. No.5,744,515; columns 13 and 14 (Method and Implantable Article forPromoting Endothelialization).

A preferred composition of this invention includes one or more pendentlatent reactive (preferably photoreactive) groups covalently attached,directly or indirectly, to either the surface of the endovascular graftcover, to the bioactive agent itself, or to a linking moeity for use inattaching an agent to a surface. Photoreactive groups are definedherein, and preferred groups are sufficiently stable to be stored underconditions in which they retain such properties. See, e.g., U.S. Pat.No. 5,002,582, the disclosure of which is incorporated herein byreference. Latent reactive groups can be chosen that are responsive tovarious portions of the electromagnetic spectrum, with those responsiveto ultraviolet and visible portions of the spectrum (referred to hereinas “photoreactive”) being particularly preferred.

Photoreactive groups respond to specific applied external stimuli toundergo active specie generation with resultant covalent bonding to anadjacent chemical structure, e.g., as provided by the same or adifferent molecule. Photoreactive groups are those groups of atoms in amolecule that retain their covalent bonds unchanged under conditions ofstorage but that, upon activation by an external energy source, formcovalent bonds with other molecules.

The photoreactive groups generate active species such as free radicalsand particularly nitrenes, carbenes, and excited states of ketones uponabsorption of electromagnetic energy. Photoreactive groups may be chosento be responsive to various portions of the electromagnetic spectrum,and photoreactive groups that are responsive to e.g., ultraviolet andvisible portions of the spectrum are preferred and may be referred toherein occasionally as “photochemical group” or “photogroup”.

Photoreactive aryl ketones are preferred, such as acetophenone,benzophenone, anthraquinone, anthrone, and anthrone-like heterocycles(i.e., heterocyclic analogs of anthrone such as those having N, O, or Sin the 10-position), or their substituted (e.g., ring substituted)derivatives. Examples of preferred aryl ketones include heterocyclicderivatives of anthrone, including acridone, xanthone, and thioxanthone,and their ring substituted derivatives. Particularly preferred arethioxanthone, and its derivatives, having excitation energies greaterthan about 360 nm.

The functional groups of such ketones are preferred since they arereadily capable of undergoing the activation/inactivation/reactivationcycle described herein. Benzophenone is a particularly preferredphotoreactive moiety, since it is capable of photochemical excitationwith the initial formation of an excited singlet state that undergoesintersystem crossing to the triplet state. The excited triplet state caninsert into carbon-hydrogen bonds by abstraction of a hydrogen atom(from a support surface, for example), thus creating a radical pair.Subsequent collapse of the radical pair leads to formation of a newcarbon-carbon bond. If a reactive bond (e.g., carbon-hydrogen) is notavailable for bonding, the ultraviolet light-induced excitation of thebenzophenone group is reversible and the molecule returns to groundstate energy level upon removal of the energy source. Photoactivatiblearyl ketones such as benzophenone and acetophenone are of particularimportance inasmuch as these groups are subject to multiple reactivationin water and hence provide increased coating efficiency.

The azides constitute a preferred class of photoreactive groups andinclude arylazides (C₆R₅N₃) such as phenyl azide and particularly4-fluoro-3-nitrophenyl azide, acyl azides (—CO—N₃) such as benzoyl azideand p-methylbenzoyl azide, azido formates (—O—CO—N₃) such as ethylazidofonmate, phenyl azidoformate, sulfonyl azides (—SO₂—N₃) such asbenzenesulfonyl azide, and phosphoryl azides (RO)₂PON₃ such as diphenylphosphoryl azide and diethyl phosphoryl azide. Diazo compoundsconstitute another class of photoreactive groups and includediazoalkanes (—CHN₂) such as diazomethane and diphenyldiazomethane,diazoketones (—CO—CHN₂) such as diazoacetophenone and1-trifluoromethyl-1-diazo-2-pentanone, diazoacetates (—O—CO—CHN₂) suchas t-butyl diazoacetate and phenyl diazoacetate, andbeta-keto-alpha-diazoacetates (—CO—CN₂—CO—O—) such as t-butyl alphadiazoacetoacetate. Other photoreactive groups include the diazirines(—CHN₂) such as 3-trifluoromethyl-3-phenyldiazirine, and ketenes(—CH═C═O) such as ketene and diphenylketene.

Upon activation of the photoreactive groups, the reagent molecules arecovalently bound to each other and/or to the material surface bycovalent bonds through residues of the photoreactive groups. Exemplaryphotoreactive groups, and their residues upon activation, are shown asfollows (where R and R′ are independently non-interfering organicradicals): Residue Photoreactive Group Functionality aryl azides amineR—NH—R′ acyl azides amide R—CO—NH—R′ azidoformates carbamateR—O—CO—NH—R′ sulfonyl azides sulfonamide R—SO₂—NH—R′ phosphoryl azidesphosphoramide (RO)₂PO—NH—R′ diazoalkanes new C—C bond diazoketones newC—C bond and ketone diazoacetates new C—C bond and esterbeta-keto-alpha- new C—C bond and beta- diazoacetates ketoesteraliphatic azo new C—C bond diazirines new C—C bond ketenes new C—C bondphotoactivated new C—C bond and alcohol ketones

Test Assay

An assay can be performed in the following manner in order to evaluatethe usefulness of a particular bioactive agent and manner of coating.The assay, based on a canine model, is used to evaluate and predict themanner and/or extent to which an endovascular graft (the cover portionof which has been treated with a bioactive agent) can preventendoleaking when positioned in vivo. The canine model has beenextensively used to evaluate the in vivo performance of vascular grafts,and Applicants have determined the manner in which the intercostalarteries in the dog provide a unique ability to evaluate endoleaking.

A standard endovascular graft is provided, e.g., in the form of ahook-less, nitinol spring graft system covered with a polymeric (e.g.,PET) material. The device cover is coated with the bioactive agent to beevaluated for use in preventing endoleaking. At the end of the implantphase (12 weeks) the animals are anesthetized and the grafts removed.Upon recovery, the grafts are processed for light microscopy.

The grafts are inserted through the femoral artery and placed in theaorta of a dog, just distal to the renal artery. After insertion, anangiogram (at about 30 minutes) is performed to evaluate perigraft bloodflow, which is visualized as blood flowing through adjacent intercostalarteries (and particularly those in the region of the aorta that arecovered by the endovascular graft). Grafts with an effective coatingwill substantially prevent both acute and long-term blood flow throughadjacent intercostal arteries. Uncoated grafts (or unsuitably coatedgrafts), by comparison, will not prevent acute perigraft blood flow;however some such grafts may prevent blood flow at 12 weeks.

In addition, the grafts and adjacent aorta are removed at 12 weeks,fixed and evaluated histologically for tissue ingrowth. Grafts with aneffective coating will preferably also have the perigraft region largelyfilled with stable tissue (smooth muscle cells and/or myofibroblasts).Uncoated grafts may have channels through which blood flows from thelumen of the aorta into the perigraft space and out through theintercostal arteries. If the dog model reproduced results observed inhuman patients, about 20-25% of the uncoated grafts at 12 weeks wouldshow perigraft blood flow during angiography and corresponding perigraftblood channels upon histological evaluation.

In evaluating and comparing uncoated (or unsuitably) coated grafts withthose coated in the manner presently described, it can be seen thatdetectable endoleaking will occur in substantially none (<5%) of coatedgrafts when evaluated one-half hour after placement (the initialangiogram). By comparison, substantially all (>95%) of the uncoated (orunsuitably) coated grafts will show detectable endoleaking. At 12 weeks,it can be seen that the coated grafts of this invention will continue toprevent detectable endoleaking in substantially all cases (i.e.,detectable endoleaking in less than 5% of the cases), as compared to theuncoated grafts, in which detectable endoleaking is likely to continuein up to 20% of the cases.

Protocol

12 Canine animals are used (conditioned mongrels, approx. 27-45 kg, mayinclude both sexes). A pretrial screen is performed to ensure the goodgeneral health status of the animals. On the day of surgery, the animalsare premedicated with a mixture of intramuscular ketamine, acepromazineand atropine. General anesthesia is induced using intravenous pentothaland the airway maintained with orotracheal intubation. Anesthesia ismaintained with a mixture of inhaled halothane and oxygen. The innerthigh is shaved and prepared with betadine. Intravenous cephalexin 500mg is given prior to the initial incision.

For deploying the graft the inner thigh is prepared for a cut-down tothe femoral artery.

Heparin is administered, 3,000 units IV, prior to catheter insertion.The femoral artery is isolated and an arteriotomy performed on theartery. A 7 to 9 FR introducer sheath is inserted in the artery. Anangiographic catheter is introduced and an angiogram is performed. Allangiographic and fluoroscopic procedures are recorded on VCR. Theaortic-iliac vasculature is mapped with the diameter of the aortameasured and location of the renal arteries determined. A guide wire isinserted and the catheter removed. The endovascular graft is theninserted over the guide wire and advanced to the proximal position belowthe renal arteries. Once the device is in the proper position, thecentral balloon catheter is withdrawn and inflated along the entirelength of the device as per the manufacturer's procedures. The deliverycatheter is removed and the sheath and angiographic catheter replaced inthe vessel. An angiogram is performed and any abnormalities areobserved. If abnormalities are observed, the balloon catheter may bereintroduced to correct the situation. The catheter, guide wire andsheath are removed and the arteriotomy repaired. The incision is closedand the dog recovered.

An additional angiogram is performed 30 minutes after implantation toevaluate perigraft blood flow, as indicated by flow through intercostalarteries in the region of the aorta that is covered by the endovasculargraft. At 12 weeks, the dogs are re-anesthetized and another angiogramis performed to evaluate perigraft blood flow. Then the grafts aresurgically recovered. The graft is exposed under aseptic sterileconditions through an abdominal midline laparotomy. Heparin isadministered IV five minutes prior to clamping of the aorta proximal anddistal to the endovascular graft. Photographs are taken of the graft insitu. The graft is excised with at least 2 cm of the aorta at bothanastomoses. The excised graft is placed in sterile buffer (Dulbecco'sCF PBS; pH 7.4 with 1% bovine serum albumin). Animals are euthanizedafter graft harvest using intravenous B-euthanasia-D® solution. Thegraft is cut into sections, placed in labeled containers withHistochoice™ fixative for light microscopy.

Each graft is stained with hematoxylin/eosin (H&E) and Masson trichrome.The samples are also immunostained for von Willebrand factor (vWF), αsmooth muscle cell actin (αSMC actin) and proliferating cell nuclearantigen (PCNA). The slides are examined and photomicrographs taken. Inaddition, the slides are analyzed for neointimal thickness. Cells bothwithin the graft and in the tissue associated with the graft arecharacterized.

Data Analysis

Angiographic evaluation of grafts with an effective coating of thisinvention will show unimpeded blood flow through the lumen of the graftbut no blood flow through adjacent intercostal artieries when evaluatedat either the initial angiogram after implantation or at 12 weeks. Inaddition, histological evaluation of such grafts at 12 weeks preferablyshows the perigraft space to be filled with a high density of cells thatstain positive with αSMC actin (smooth muscle cells and/ormyofibroblasts). The perigraft space around such grafts lacks channelsthat would allow blood to flow from the aorta to the intercostalarteries. The lumen of such grafts does not contain sufficient thrombusor layers of cells to significantly reduce blood flow through the aorta.Uncoated grafts or grafts with unsuitable coatings produce two types ofdetrimental features, namely either: 1) blood flow from the aortathrough channels in the perigraft space and into intercostal arteries,and/or 2) the formation of thrombus or excessive layers of cells on theluminal surface, which significantly decreased blood flow through theaorta.

The invention will be further described with reference to the followingnon-limiting Example. It will be apparent to those skilled in the artthat many changes can be made in the embodiments described withoutdeparting from the scope of the present invention. Thus the scope of thepresent invention should not be limited to the embodiments described inthis application, but only by embodiments described by the language ofthe claims and the equivalents of those embodiments. Unless otherwiseindicated, all percentages are by weight.

EXAMPLE

Four dogs were studied in the manner described above, with two dogsreceiving uncoated grafts and two receiving grafts coated with collagen.

Bovine skin collagen (Semed S Powder) was purchased from Kensey NashCorporation (Exton, Pa.). This collagen has the proportions of type 1collagen (95%) and type III collagen (5%) that are usual forskin-derived collagens. Such collagen is abbreviated below as Col I—S.Col I—S was photoderivatized by the addition of (benzoylbenzoicacid)-(epsilon aminocaproic acid)-(N-oxysuccinimide) (BBA-EAC-NOS) andradiolabeled using protocols described in U.S. Pat. No. 5,744,515(columns 13 and 14). Photoderivatized Col I—S is abbreviated below asphoto-Col I—S.

The coating procedure consisted of immersing endovascular grafts in asolution of photo-Col I—S, removing the grafts, and illuminating for 2.5minutes at 320 to 340 nm to activate the BBA moieties and producecovalent coupling. The above coating steps were repeated to generate 2coats of photo-Col I—S. The coated grafts were then washed in sterilephosphate buffered saline (PBS) to remove loosely adherent photo-ColI—S, sterilized by soaking for 30 minutes in 70% ethanol, and washed insterile PBS to remove ethanol. Coated grafts were stored prior toimplantation at 4° C. in PBS plus antibiotics (10 units penicillin G, 10μg steptromycin, 0.025 μg amphotericin B per ml.).

The amount of immobilized photo-Col I—S was quantitated by applyingtritium-labeled photo-Col I—S as described above and measuring retainedcounts via standard liquid scintillation spectrometry methods. Theamount of immobilized photo-Col I—S was found to be 1.8 μg of photo-ColI—S per square cm of endovascular graft material. The coating processcan be shown to immobilize photo-Col-I—S in a conformal manner, in thatthe coating is substantially uniform in coverage, but does notsignificantly fill the pores between adjacent polymer fibers (less than10% of the pore volume is filled by the coating material). Coatingconformity can be evalutated by staining coated grafts with FITC(fluorescein-5-isothiocyanate) and viewing the stained grafts viafluorescence microscopy. When stained and viewed in this manner theindividual polymer fibers of the coated endovascular grafts appearuniformly green in color, with the spaces between such fibers appearingblack (i.e., unfilled).

During the implant procedures all devices deployed easily. The use of aballoon catheter following initial deployment completed the expansion ofthe devices. Angiograms performed following device deployment revealedunimpeded flow through the lumen of each of the devices. Endoleaking wasnot detected in either of the coated grafts, but was detected in both ofthe uncoated grafts, as evidenced by contrast agent present in branchvessels off the aorta. Comparison of device position, both before andafter re-establishment of blood flow, indicated that all devicesremained in their initial position with no evidence of device movementwithin the aorta. At the time of device explantation (12 weeks), arepeat angiogram was performed. Neither coated nor uncoated graftsshowed blood flow through intercostal arteries, evidence of grosslumenal thickening, or loss of lumenal patency.

All explant samples were subjected to histologic evaluation whichincluded hematoxylin and eosin (H&E) staining, and immunocytochemicalevaluation of von Willebrand factor positive cells (endothelium), alphasmooth muscle cell actin positive cells (smooth muscle/myofibroblasts),and proliferating cell nuclear antigen positive cells (cellproliferation/hyperplasia).

Microscopic evaluation of H&E stained sections revealed no significantdifference between coated and uncoated grafts. A cellular lining(defined as a neointima) was evident on all samples; however thethickness of the neointima was not sufficient to significantly decreasethe lumenal diameter. No thrombus formation was observed.

Immunocytochemistry confirmed the presence of endothelial cells on thelumenal surface (positive staining with vWF antibodies). The cell layersunder the endothelium (in the neointima, within the fibers of the graft,and in the perivascular space) were composed predominantly of cells thatstained positive with antibodies to αSMC actin, suggesting thepredominance of smooth muscle cells or myofibroblasts.

1. An endovascular graft comprising an expandable stent portion and astent cover portion, wherein the stent cover portion comprises a porous,fibrous material having both an outer perigraft surface and an innerluminal surface, and is coated on at least the outer surface with ahemostatic bioactive agent covalently attached by the activation ofphotoreactive groups provided by the stent cover portion, by thebioactive agent itself, and/or by a linking agent wherein the bioactiveagent is attached to the fibers of the material without occluding itspores.
 2. (canceled)
 3. A graft according to claim 1 wherein the stentcover portion is prepared from a porous material selected from PET andePTFE and the bioactive agent comprises hemostatic collagen. 4-5.(canceled)
 6. A graft according to claim 1 wherein the agent is selectedfrom the group consisting of proteins having a specific hemostaticeffect, and positively charged compounds having a nonspecific effect. 7.A graft according to claim 6 wherein the agent comprises a protein orthe active portions and domains of a protein selected from the groupconsisting of collagen, thrombin, fibrinogen, elastin, and vonWillebrand factor. 8-10. (canceled)
 11. A method of preparing anendovascular graft comprising an expandable stent portion and a stentcover portion, comprising the step of coating at least the outer surfaceof the stent cover portion with a hemostatic bioactive agent that iscovalently attached by the activation of photoreactive groups providedby the stent cover portion, by the bioactive agent, and/or by a linkingagent.
 12. (canceled)
 13. A method according to claim 11 wherein thestent cover portion is prepared from a porous material selected from PETand ePTFE and the bioactive agent comprises hemostatic collagen. 14-15.(canceled)
 16. A method according to claim 11 wherein the agent isselected from the group consisting of proteins having a specifichemostatic effect, and positively charged compounds having a nonspecifichemostatic effect.
 17. A method according to claim 16 wherein the agentcomprises a protein or the active portions and domains of a proteinselected from the group consisting of hemostatic collagen, thrombin,fibrinogen, elastin, and von Willebrand factor. 18-20. (canceled)
 21. Amethod of preventing endoleaking in the course of deploying and using anendovascular graft that comprises an expandable stent portion and astent cover, the method comprising the step of first coating the stentcover by a method that comprises the step of coating at least the outersurface of the stent cover portion with a hemostatic bioactive agentthat is covalently attached by the activation of photoreactive groupsprovided by the stent cover portion, by the bioactive agent, and/or by alinking agent.
 22. A method according to claim 21 wherein the stentcover portion is prepared from a porous material selected from PET andePTFE and the bioactive agent comprises hemostatic collagen.
 23. Amethod according to claim 21 wherein the agent is selected from thegroup consisting of proteins having a specific hemostatic effect, andpositively charged compounds having a nonspecific hemostatic effect. 24.A method according to claim 23 wherein the agent comprises a protein orthe active portions and domains of a protein selected from the groupconsisting of hemostatic collagen, thrombin, fibrinogen, elastin and vonWillebrand factor.
 25. A method according to claim 21 wherein theendovascular graft comprises an expandable stent portion and a porousstent cover portion selected from PET and ePTFE, and the bioactive agentcomprises a protein or the active portions and domains of a proteinselected from the group consisting of hemostatic collagen, thrombin,fibrinogen, elastin and von Willebrand factor.
 26. A method according toclaim 21 wherein the coating is provided on the perigraft, as opposed toluminal, surface of the stent cover.
 27. A method according to claim 21wherein the coating adds about 5%, or less, to the original thickness ofthe material used as the stent cover portion.
 28. A method according toclaim 21 wherein the bioactive agent used to coat the surface is itselfphotoderivatized.
 29. A method according to claim 21 wherein the stentcover portion is prepared from a porous material selected from PET andePTFE, the agent comprises a protein or the active portions and domainsof a protein selected from the group consisting of hemostatic collagen,thrombin, fibrinogen, elastin and von Willebrand factor, the coating isprovided on the perigraft, as opposed to luminal, surface of the stentcover and adds about 5%, or less, to the original thickness of thematerial used as the stent cover portion.
 30. A method according toclaim 29 wherein the bioactive agent used to coat the surface is itselfphotoderivatized.
 31. A method of preventing endoleaking in the courseof deploying and using an endovascular graft, the method comprising thesteps of: a) providing an endovascular graft comprising an expandablestent portion and a stent cover portion, wherein the stent cover portioncomprises a porous, fibrous material having both an outer perigraftsurface and an inner luminal surface, the cover portion having ahemostatic bioactive agent on at least the outer surface covalentlyattached to the fibers of the material without occluding its pores, bythe activation of photoreactive groups provided by the stent coverportion, by the bioactive agent, and/or by a linking agent, and b)implanting the graf in a vessel in a manner that avoids endoleaking. 32.A method according to claim 31 wherein the stent cover portion isprepared from a porous material selected from PET and ePTFE and thebioactive agent comprises hemostatic collagen.
 33. A method according toclaim 31 wherein the agent is selected from the group consisting ofproteins having a specific hemostatic effect, and positively chargedcompounds having a nonspecific hemostatic effect.
 34. A method accordingto claim 33 wherein the agent comprises a protein or the active portionsand domains of a protein selected from the group consisting ofhemostatic collagen, thrombin, fibrinogen, elastin and von Willebrandfactor.
 35. A method according to claim 31 wherein the endovasculargraft comprises an expandable stent portion and a porous stent coverportion selected from PET and ePTFE, and the bioactive agent comprises aprotein or the active portions and domains of a protein selected fromthe group consisting of hemostatic collagen, thrombin, fibrinogen,elastin and von Willebrand factor.
 36. A method according to claim 31wherein the coating is provided on the perigraft, as opposed to luminal,surface of the stent cover.
 37. A method according to claim 31 whereinthe coating adds about 5%, or less, to the original thickness of thematerial used as the stent cover portion.
 38. A method according toclaim 31 wherein the bioactive agent used to coat the surface is itselfphotoderivatized.
 39. A method according to claim 31 wherein the stentcover portion is prepared from a porous material selected from PET andePTFE, the agent comprises a protein or the active portions and domainsof a protein selected from the group consisting of hemostatic collagen,thrombin, fibrinogen, elastin and von Willebrand factor, the coating isprovided on the perigraft, as opposed to luminal, surface of the stentcover and adds about 5%, or less, to the original thickness of thematerial used as the stent cover portion.
 40. A method according toclaim 39 wherein the bioactive agent used to coat the surface is itselfphotoderivatized.
 41. A method according to claim 31 wherein the agentis immobilized in an amount between about 0.05 μg/cm² to about 10μg/cm².
 42. A method according to claim 31 wherein the endovasculargraft is provided in the form of a collapsed small diameter tube of onthe order of two mm or less overall diameter, and can be expanded toform a larger diameter tube in situ of between about six mm and aboutthirty mm.
 43. A method according to claim 39 wherein the bioactiveagent used to coat the surface is itself photoderivatized, and isimmobilized in an amount between about 0.05 μg/cm² to about 10 μg/cm²,and wherein the endovascular graft is provided in the form of acollapsed small diameter tube of on the order of two mm or less overalldiameter, and can be expanded to form a larger diameter tube in situ ofbetween about six mm and about thirty mm.
 44. A graft according to claim1 wherein the bioactive agent is attached to the surface in the form ofa thin, conformal coating and adds no more than 25% to the originalthickness of the material used as the stent cover portion.
 45. A graftaccording to claim 1 wherein the bioactive agent is immobilized in arange of about 0.01 μg/cm² to about 50 μg/cm².